Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), BSE and chronic wasting disease (CWD). Our project is aimed at understanding and thwarting the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using cell culture and cell-free systems we have 1) identified tetrapyrroles as a new class of inhibitors of PrP-res formation, 2) demonstrated a need for an intact disulfide bond in PrP for its conversion to PrP-res, 3) demonstrated that different conformations of PrP-res are associated with different TSE strains in hamsters, 4) analyzed the structure-function aspects of Congo red, a known inhibitor of PrP-res formation, 5) developed a new cell-free assay for monitoring the binding interactions between PrP-res and normal PrP that lead to conversion of the latter into the former and 6) assessed the ability of PrP-res from CWD-infected deer and elk to induce the conversion of normal PrP from humans, cattle and other species to PrP-res. - Transmissible spongiform encephalopathies, prions, neurodegeneration, chronic wasting disease, scrapie, Creutzfeldt-Jakob disease